The invention relates to a device for the time-controlled administration of the anesthetic propofol by means of a procedure for the determination of an appropriate dose profile and corresponding control of an infusion pump acting as a metering unit.
Many medical interventions, particularly invasive surgical interventions, can only be carried out under general anesthesia. Exact time-controlled administration of the anesthetic is crucial to the safety of the patient and the success of the treatment. Ideally, the course of anesthesia should have a rectangular profile, i.e. anesthesia should be induced rapidly at an exactly defined time, then remain approximately constant over a certain period and, after completion of the intervention, be terminated just as quickly. An anesthetic must be administered at an appropriate infusion rate, which varies over time. To this end, medicine uses electronically controlled infusion pumps, which permit programming of the infusion rate. However, this is complicated by the fact that the time/effect profile of the anesthetic, which determines the course of anesthesia, is influenced both by the infusion rate and by a series of patient-related anatomical, physiological, biochemical, and genetic factors. As soon as the anesthetic enters the patient's systemic circulation the substance undergoes distribution in the body. The anesthetic is transported in the bloodstream to various organs, where it finally passes into the cells. These organ distribution kinetics are determined e.g. by the individual blood flow rates in the different organs, which can be substantially different from typical healthy adults in certain subpopulations (e.g. children, the elderly, diseased patients, pregnant women). In addition, the clearance, that is the rate of metabolism in the excretory organ (mostly the liver, in part other organs such as the intestine or kidney as well), determines the elimination kinetics, which are of central significance to the maintenance and termination of the anesthesia. This clearance is also highly dependent on individual factors in the patients concerned, e.g. age, sex, level of expression of metabolizing enzymes and rate of blood flow through the eliminating organ.
From a pharmacodynamic viewpoint, it is the time course of the concentration of the anesthetic at its site of action, the brain, which is of particular interest, as this determines the course of anesthesia.
Computer-controlled infusion pumps with input functions determined using a pharmacokinetic model are known from the prior art and are commercially available under the term “TCI” (=target controlled infusion). The main application of TCI is the control of intravenous administration of the anesthetic propofol.
U.S. Pat. No. 5,609,575 describes a TCI system in which the dose-concentration routine uses the body weight index as the only patient parameter in the system and only achieves a rough simulation of the concentration. There is a commercial system for the control of infusion pumps for the anesthetic propofol, marketed as Diprifusor™ from AstraZeneca—product information “Diprifusor™: Target Controlled Infusion (TCI) in anaesthetic practice”, AstraZeneca Anaesthesia, New Edition (1998). Another infusion system specifically for use in children is in development (Paedfusor, Munoz H R, Cortinez L I, Ibacache M E, Altmann C. Estimation of the plasma effect site equilibration rate constant (ke0) of propofol in children using the time to peak effect. Anesthesiology 2004; 101:1269-74). In the prior art, the pharmacokinetic profile of propofol, i.e. its spread and distribution as a function of time after administration, is described by an open three-compartment model (Gepts E, Camu F, Cockshott I D, Douglas E J. Disposition of propofol administered as constant rate intravenous infusions in humans. Anesth Analg 1987; 66(12):1256-63; Munoz H R, Cortinez L I, Ibacache M E, Altmann C. Estimation of the plasma effect site equilibration rate constant (ke0) of propofol in children using the time to peak effect. Anesthesiology 2004; 101:1269-74). The central compartment in this three compartment model represents the blood pool, one peripheral compartment is the so-called “effect compartment” which describes the time course of the concentration of the anesthetic at its site of action, and the third compartment represents organs with low blood perfusion, which cause slow redistribution of the anesthetic, which affects its elimination. Patient-related input parameters in this system are the age, body weight and a target concentration in the patient's blood. The infusion rate to be used is calculated from these on the basis of an open three-compartment model fitted to experimental data. The parameters in this three-compartment model (volumes of the compartments, mass-transfer rates, and elimination rates) are age and/or body-weight dependent. Of central significance to the entire system is the transport rate between the central (blood) compartment and the effect compartment (ke0), which ultimately regulates the time course of propofol at its site of action and thus the course of anesthesia. Several such parameter sets for propofol have been published in the literature (Kazama T, Ikeda K, Morita K, Kikura M, Ikeda T, Kurita T et al. Investigation of effective anesthesia induction doses using a wide range of infusion rates with undiluted and diluted propofol. Anesthesiology 2000; 92(4):1017-28; Munoz H R, Cortinez L I, Ibacache M E, Altmann C. Estimation of the plasma effect site equilibration rate constant (ke0) of propofol in children using the time to peak effect. Anesthesiology 2004; 101:1269-74). The underlying three-compartment model can be found on the internet and is publicly accessible (TIVA-Trainer, available under www.eurosiva.org).
The disadvantage of this known device is that these fitted model parameters are only average values representing the patients in the underlying experimental study. Although these models can take into account the dependency of the parameters on body weight and, in part, age as well, there is no possibility of more extensive individualization and adjustment of the pharmacokinetic model parameters to specific patients. Thus, the open three-compartment models described are unable to allow for the physiological peculiarities of specific patient groups, e.g. children or the elderly or diseased patients. An example of this is the nonlinear age-dependency of blood flow in the brain (the target organ of propofol) in children. The body-weight-normalized blood flow rate in a two-year-old child is twice as high as in a five-year-old child (Wintermark M, Lepori D, Cotting J, Roulet E, van M G, Meuli R et al. Brain perfusion in children: evolution with age assessed by quantitative perfusion computed tomography. Pediatrics 2004; 113(6):1642-52), a fact which cannot be described by an age-independent mass-transfer rate in the effect compartment (Ke0). Equally, age-related differences in the composition of the body (in respect of its relative proportions of water, fat, and protein) very substantially influence the volume of distribution, and thus the kinetics, of propofol. Similarly, the pharmacokinetics of propofol in obese patients does not just depend on the body weight, but rather the proportion of fat. In the elderly and in diseased patients—but also in children—differences in the metabolic rate decisively influence the propofol level in the blood and brain. The volume of the central compartment is similar in obese and normal-weight people, which can be explained by the comparatively low variability of the volume of well-perfused tissue between such individuals. On the other hand, the peripheral compartments, in particular that which represents poorly perfused tissue, are distinctly different, which leads to a larger volume of distribution in the obese. As a result, the times for the induction of general anesthesia are similar, but recovery is faster in obese patients (Servin F, Farinotti R, Haberer J, Desmonts J. Propofol infusion for maintenance of anesthesia in morbidly obese patients receiving nitrous oxide. Anesthesiology 2005; 78:657-65). Behavior similar to that in the obese has been observed in neonates, in whom the volume of the peripheral compartment is also relatively larger than that in adults, which can be explained by the relatively high proportion of body fat in neonates. Neonates also wake more quickly from general anesthesia after the end of propofol infusion, but they recover only relatively slowly from the sequelae, which can be attributed to a reduced systemic clearance (Rigby-Jones A E, Nolan J A, Priston M J, Wright P, Sneyd R, Wolf A R. Pharmacokinetics of propofol infusions in critically ill neonates, infants, and children in an intensive care unit. Anesthesiology 2002; 97:1393-400).
The influence of such physiological, anatomical, and biochemical or genetic peculiarities on the course of anesthesia is only inadequately described with the device known from the prior art. The use of an open three-compartment model limits the flexibility to take into account different conditions of the patient such as age-dependent differences in body composition, blood flow rates and the metabolic rate, obesity, or pregnancy, etc.
Lewitt et al. describe a physiology-based pharmacokinetic model for the simulation of plasma pharmacokinetics of propofol after intravenous administration (Levitt D G, Schnider T W., Human physiologically based pharmacokinetic model for propofol. BMC Anesthesiol. 2005 Apr. 22; 5(1):4). The model provides a good description of the concentration/time course of propofol in the plasma of adult patients, but does not describe the extent to which the concentrations in the brain calculated using the model reflect the actual time course of the effect of propofol. The usefulness of this model is further limited by the fact that only the fat content of the patient based on an empirical correlation equation and the propofol clearance are included as individual parameters. More extensive patient-individual parameterization is not performed. In particular, individual differences in the blood flow rates to peripheral organs, which have a substantial influence on the entire distribution kinetics of substances with rapid distribution such as propofol, are not taken into account. Simulation of the propofol pharmacokinetics in children using the model published by Levitt et al. is not possible either, as the model only describes average physiological parameters for adults. Furthermore, Lewitt et al. only describe a model for the simulation of plasma pharmacokinetics of propofol, not a device for the time-controlled administration of propofol.
The purpose of the invention is to develop an improved device, starting from the prior art described, which would permit exact time-controlled administration of propofol taking into account individual physiological, anatomical, biochemical, and genetic factors of the patient.